Abstract:

Provided are dispersions which comprise more than about (40) percent by
weight of an organic peroxide which is normally solid, an effective
dispersing amount of a pharmaceutically acceptable dispersing agent and
water. The water and about (40) percent or more peroxide forms a paste.
Addition of the dispersing agent/surfactant to a non-flowing organic
paste resulted in the formation of a shear thinning aqueous dispersion.
The aqueous dispersions can also contain optional components such as
thickening agents and anionic emulsifiers.

Claims:

1. An aqueous dispersion comprising about 40% by weight or more of an
organic peroxide and about 0.5 to 2.0% by weight of a pharmaceutically
acceptable surfactant.

11. The aqueous dispersion of claim 10 wherein said sorbitan fatty acid
ester is selected from the group consisting of sorbitan laurate, sorbitan
oleate, sorbitan palmitate and sorbitan stearate.

12. The aqueous dispersion of claim 9 wherein said amphoteric surfactant
is selected from the group consisting of sodium N-dodecyl-beta-alanin-e,
sodium N-lauryl-beta-iminodipropionate, myristoamphoacetate, lauryl
betaine and lauryl sulfobetaine.

13. The aqueous dispersion of claim 9 wherein said anionic surfactant is
selected from the group consisting of sarcosinates, sulfates,
isethionates, taurates, phosphates, lactylates, glutamates and mixtures
thereof.

14. The aqueous dispersion of claim 9 wherein said anionic surfactant is
selected from the group consisting of water-soluble salts of the organic,
sulfuric acid reaction products of the general formula:
R1--SO3-M wherein R1 is chosen from the group consisting
of a straight or branched chain, saturated aliphatic hydrocarbon radical
having from about 8 to about 24 carbon atoms; and M is a cation.

15. The aqueous dispersion of claim 14, wherein said saturated aliphatic
hydrocarbon radical has from 10 to about 16 carbon atoms.

16. The aqueous dispersion of claim 9 wherein said anionic surfactant is
selected from the group consisting of succinamates, olefin sulfonates
having about 12 to about 24 carbon atoms, and b-alkyloxy alkane
sulfonates.

17. The aqueous dispersion of claim 9 wherein said anionic surfactant is
selected from the group consisting of alkanoyl sarcosinates of the
formula RCON(CH3)CH2CH2CO2M wherein R is alkyl or
alkenyl of about 10 to about 20 carbon atoms, and M is a water-soluble
cation.

18. The aqueous dispersion of claim 17 wherein said alkanoyl sarcosinate
is selected from the group consisting of ammoniumamine, sodiumamine,
potassiumamine and alkanolamine.

20. The aqueous dispersion of claim 9 wherein said taurate is selected
from the group consisting of ammonium, sodium, potassium and alkanolamine
salts of: lauroyl methyl taurate, myristoyl methyl taurate, and cocoyl
methyl taurate and N-alkyltaurine.

21. The aqueous dispersion of claim 9 wherein said lactylate is selected
from the group consisting of ammonium, sodium, potassium and alkanolamine
salts of: lauroyl lactylate, cocoyl lactylate, lauroyl lactylate, and
caproyl lactylate.

22. The aqueous dispersion of claim 9 wherein said glutamate is selected
from the group consisting of ammonium, sodium, potassium and alkanolamine
salts of: lauroyl glutamate, myristoyl glutamate, and cocoyl glutamate.

Description:

FIELD OF INVENTION

[0001] The present invention relates to pharmaceutically acceptable
aqueous dispersions of normally solid organic peroxides. The dispersions
are pastes which contain high concentrations of the peroxide. The pastes
are shear thinning so as to be pumpable/pourable when mixed or stirred
which makes their handling and use easier.

BACKGROUND

[0002] Peroxides have, as a general property, a tendency to be flammable
and explosive with some peroxides exhibiting such properties to a greater
extent than others. For example, benzoyl peroxide may decompose when dry
due to shock, friction, or static electricity. This property carries with
it the obvious hazards to the users of these materials as well as to the
manufacturers and intermediate handlers thereof. One particularly
burdensome aspect of this property occurs during shipment of the
peroxides. Accordingly, it has long been an object to provide flame
resistant organic peroxide compositions. For example, U.S. Pat. No.
3,507,800 is directed to providing a flame resistant peroxide composition
consisting essentially of three components--water, peroxide and solvent
wherein the water is at least about 18 percent of the composition.

[0003] The safety and end-use advantage provided by water-soluble or
water-emulsifiable peroxides is recognized. U.S. Pat. No. 3,825,509
describes a process for the suspension polymerization of vinyl chloride
wherein the initiator is an aqueous emulsion of an organic peroxide in
which the peroxide is present in an amount up to 19 weight percent. The
surfactant used to prepare the aqueous peroxide emulsion is a combination
of polyvinyl alcohol and polyoxyethylene sorbitan monolaurate. However,
emulsions containing greater than about 19 percent by weight of organic
peroxide are described as being too viscous and therefore difficult to
handle.

[0004] There have been attempts in the past to make peroxide dispersions.
U.S. Pat. Nos. 4,039,475 and 4,092,470 disclose stable, pumpable aqueous
suspensions of organic peroxides using a mixture of a) nonionic
emulsifiers having a maximum HLB value of 12.5 and b) nonionic
emulsifiers having a minimum HLB value of 12.5 or anionic emulsifiers.
U.S. Pat. No. 4,734,135 discloses aqueous suspensions of solid organic
peroxides using a protective colloid, a surface active agent and water.
U.S. Pat. No. 4,440,885 teaches emulsions of a solid organic peroxide
using an emulsifier having an HLB value from about 9 to about 20, a
hydrocarbon solvent and water.

[0005] Numerous other dispersions of solid organic peroxides are to be
found in the art. Yet there is still a need for pharmaceutically
acceptable aqueous dispersions containing high concentrations of solid
organic peroxides that are pumpable/pourable.

SUMMARY OF THE INVENTION

[0006] The present aqueous dispersions comprise more than about 40 percent
by weight of an organic peroxide which is normally solid, an effective
dispersing amount of a pharmaceutically acceptable dispersing agent and
water. It was discovered that the addition of a dispersing
agent/surfactant to a non-flowing organic paste resulted in the formation
of a shear thinning aqueous dispersion. The aqueous dispersions can also
contain optional components such as thickening agents and anionic
emulsifiers.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0007] Aqueous dispersions of the present invention comprise an organic
peroxide which is normally solid and a pharmaceutically acceptable
dispersing agent/surfactant.

[0009] The present aqueous dispersions comprise about 40 percent or more
by weight of an organic peroxide. One of the features of the present
invention is that it enables the preparation of aqueous dispersions
containing about 40 or more percent by weight of organic peroxide which
dispersions are pumpable because they are shear thinning. Heretofore it
has been difficult to make pumpable dispersions containing about 40 or
more percent by weight organic peroxide. In this description, shear
thinning means that viscosity drops as the shear rate increases. Thus,
the viscosity of the peroxide dispersions of the present invention will
drop as the dispersion is stirred or mixed and it becomes pourable or
pumpable easing use.

[0010] A pharmaceutically acceptable dispersing agent refers to a
dispersing agent that does not cause significant irritation to an
organism and does not abrogate the biological activity and properties of
an administered compound that the dispersion of the present invention is
combined with.

[0011] Besides the water and organic peroxide, the composition of the
present invention also comprise one or more pharmaceutically acceptable
dispersing agents or surfactants in an amount of from about 0.5 to 2.0 wt
%. A wide variety of pharmaceutically acceptable dispersing agents are
useful herein and include those selected from the group consisting of
anionic surfactants, nonionic surfactants, amphoteric surfactants, and
mixtures thereof.

[0013] Nonlimiting examples of amphoteric pharmaceutically acceptable
dispersing agents or surfactants useful in the composition of the present
invention include those selected from the group consisting of sodium
N-dodecyl-beta-alanin-e, sodium N-lauryl-beta-iminodipropionate,
myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

[0014] Nonlimiting examples of anionic pharmaceutically acceptable
dispersing agents or surfactants useful in the compositions of the
present invention include those selected from the group consisting of
sarcosinates, sulfates, isethionates, taurates, phosphates, lactylates,
glutamates, and mixtures thereof. Another suitable class of anionic
surfactants are the water-soluble salts of the organic, sulfuric acid
reaction products of the general formula: R1-SO3-M wherein R1 is
chosen from the group consisting of a straight or branched chain,
saturated aliphatic hydrocarbon radical having from about 8 to about 24,
preferably about 10 to about 16, carbon atoms; and M is a cation. Still
other anionic synthetic surfactants include the class designated as
succinamates, olefin sulfonates having about 12 to about 24 carbon atoms,
and b-alkyloxy alkane sulfonates. Examples of these materials are sodium
lauryl sulfate and ammonium lauryl sulfate.

[0015] Other anionic materials include phosphates such as monoalkyl,
dialkyl, and trialkylphosphate salts.

[0016] Other anionic materials include alkanoyl sarcosinates corresponding
to the formula RCON(CH3)CH2CH2CO2M wherein R is alkyl
or alkenyl of about 10 to about 20 carbon atoms, and M is a water-soluble
cation such as ammonium, sodium, potassium and alkanolamine (e.g.,
triethanolamine), a preferred examples of which are sodium lauroyl
sarcosinate, sodium cocoyl sarcosinate, ammonium lauroyl sarcosinate, and
sodium myristoyl sarcosinate. TEA salts of sarcosinates are also useful.

[0017] Also useful as pharmaceutically acceptable dispersing agents are
taurates which are based on taurine, which is also known as
2-aminoethanesulfonic acid. Especially useful are taurates having carbon
chains between C8 and C16. Examples of taurates include
N-alkyltaurines such as the one prepared by reacting dodecylamine with
sodium isethionate according to the teaching of U.S. Pat. No. 2,658,072
which is incorporated herein by reference in its entirety. Further
nonlimiting examples include ammonium, sodium, potassium and alkanolamine
(e.g., triethanolamine) salts of lauroyl methyl taurate, myristoyl methyl
taurate, and cocoyl methyl taurate.

[0021] An aqueous solution of 50% by weight benzoyl peroxide and 0.25% by
weight polysorbate 20 was prepared and allowed to stand for two weeks.
Viscosity was measure with a Brookfield viscometer, using an RV-3 spindle
at 10 rpm at 20° C. The viscosity after standing was about
8,5000-10,000 centipoise. After vigorous shaking the viscosity dropped to
about 2,450-3,100 centipose.

Example 2

[0022] Aqueous solutions of 50% by weight benzoyl peroxide were prepared
having 0, 0.25, 0.50 and 1.00% by weight polysorbate 20. The viscosity of
each solution was measured with a Brookfield viscometer using a TC
spindle at 1.5 rpm at 20° C., helipath. The viscosities are
summarized in Table 1.